The genomes of S-phase cells are especially vulnerable to DNA damage, and problems that arise during DNA replication are a significant source of genomic instability, an important hallmark of cancer. DNA helicases play an important role in counteracting these destabilizing events. This is emphasized by the fact that mutations in many of the helicase genes are associated with cancer predisposition and premature aging syndromes, and cells from these patients harbor a high level of genomic instability [1]. SNPs and mutations in the conserved DNA helicase gene RTEL have been associated with a variety of cancers and with forms of the telomere instability disorder dyskeratosis congenita [2-5] This proposal seeks to elucidate the DNA repair functions of the RTEL helicase with the ultimate goal of better understanding mechanisms of disease development in pathologies associated with genetic defects in RTEL and other DNA helicases. RTEL function has been explored through observations in patients' cells as well as studies in mouse and other animal models, which revealed roles in telomere length maintenance. In addition, previous studies have suggested roles for RTEL in counteracting mitotic crossovers, which can lead to loss of heterozygosity, through the homologous recombination pathway and in the repair of DNA crosslinks at replication forks. Despite these findings, the embryonic lethality of the mouse model and lack of in vivo DNA repair assays has limited the study of the DNA repair roles of RTEL. In addition to the many molecular genetic tools available, the fruit fly Drosophila melanogaster is an ideal animal model to study RTEL function due to the non-canonical structure of the fly telomeres, likely allowing for the examination of genome maintenance functions separately from the telomere- specific functions. The overall goal of this research is to elucidate RTEL biological function in DNA repair and understand how RTEL protects against the deleterious biological consequences of DNA damage including defective proliferation and death. To that end, the specific aims of this proposal are to (1) test models for RTEL function in homologous recombination, (2) test models for RTEL function in replication fork progression, and (3) determine the role of RTEL in promoting proper cellular proliferation, cell cycle progression, and viability.